Fatty acid synthase (FAS) activity is a potential therapeutic target to treat cancer and obesity. Here, we have identified a molecular link between FAS andHER2(erbB-2) oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185^HER2oncoprotein expression and tyrosine-kinase activity in breast and ovarianHER2overexpressors. Similarly, p185^HER2expression was dramatically down-regulated when FAS gene expression was silenced by using the highly sequence-specific mechanism of RNA interference (RNAi). Pharmacological and RNAi-mediated silencing of FAS specifically down-regulatedHER2mRNA and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional repressor ofHER2. A cytoplasmic redistribution of p185^HER2was associated with marked morphological changes of FAS RNAi-transfected cells, whereas chemical inhibitors of FAS promoted a striking nuclear accumulation of p185^HER2. The simultaneous targeting of FAS andHER2by chemical FAS inhibitors and the humanized antibody directed against p185^HER2trastuzumab, respectively, was synergistically cytotoxic towardHER2overexpressors. Similarly, concurrent RNAi-mediated silencing of FAS andHER2genes synergistically stimulated apoptotic cell death inHER2overexpressors. p185^HER2was synergistically down-regulated after simultaneous inhibition of FAS andHER2by either pharmacological inhibitors or small interfering RNA. These findings provide evidence of an active role of FAS in cancer evolution by specifically regulating oncogenic proteins closely related to malignant transformation, strongly suggesting thatHER2oncogene may act as the key molecular sensor of energy imbalance after the perturbation of tumor-associated FAS hyperactivity in cancer cells.

Autophagy is a highly conserved cellular process by which cytoplasmic components are sequestered in autophagosomes and delivered to lysosomes for degradation. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis as well as remodeling during normal development, and dysfunctions in autophagy have been associated with a variety of pathologies including cancer, inflammatory bowel disease and neurodegenerative disease. Stem cells are unique in their ability to self-renew and differentiate into various cells in the body, which are important in development, tissue renewal and a range of disease processes. Therefore, it is predicted that autophagy would be crucial for the quality control mechanisms and maintenance of cellular homeostasis in various stem cells given their relatively long life in the organisms. In contrast to the extensive body of knowledge available for somatic cells, the role of autophagy in the maintenance and function of stem cells is only beginning to be revealed as a result of recent studies. Here we provide a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells. We discuss how recent studies of different knockout mice models have defined the roles of various autophagy genes and related pathways in the regulation of the maintenance, expansion and differentiation of various stem cells. We also highlight the many unanswered questions that will help to drive further research at the intersection of autophagy and stem cell biology in the near future.

Metformin: Multi-faceted protection against cancer